This invention relates to an optically pure androgen mediator, pharmaceutical compositions containing the stereoisomer and the use of the stereoisomer to aid in the prevention and restoration of, for example, age-related decline in muscle mass and strength and the treatment of conditions which present with low bone mass in mammals, including humans.
The worldwide population over 65 years of age is the most rapidly expanding segment of the population. A significant problem for the elderly is the decline in muscle mass and strength leading to frailty, the loss of independence, and eventual institutionalization. In the U.S. today, 1.5 million persons aged 65+ years are institutionalized and 33% of these individuals are put into long term healthcare facilities solely due to their physical frailty and their inability to maintain perquisite activities of daily living. The frail elderly are in need of a therapy either to prevent or restore the loss of age-related muscle mass and strength. There are no therapies currently approved for the treatment of frailty. Further, the only option available to the physician is androgen replacement therapy, but its non-selective tissue action has resulted in many unacceptable side effects.
Concomitant with the age-related decline in muscle mass and strength is the loss of bone mass. Osteoporosis is a systemic skeletal disease, characterized by low bone mass and deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. In the U.S., the condition affects more than 25 million people and causes more than 1.3 million fractures each year, including 500,000 spine, 250,000 hip and 240,000 wrist fractures annually. Hip fractures are the most serious consequence of osteoporosis, with 5-20% of patients dying within one year, and over 50% of survivors being incapacitated.
The elderly are at greatest risk of osteoporosis, and the problem is therefore predicted to increase significantly with the aging of the population. worldwide fracture incidence is forecasted to increase three-fold over the next 60 years, and one study estimated that there will be 4.5 million hip fractures worldwide in 2050.
Women are at greater risk of osteoporosis than men. Women experience a sharp acceleration of bone loss during the five years following menopause. Other factors that increase the risk include smoking, alcohol abuse, a sedentary lifestyle and low calcium intake.
There are currently two main types of pharmaceutical therapy for the treatment of osteoporosis. The first is the use of anti-resorptive compounds to reduce the resorption of bone tissue.
A second type of pharmaceutical therapy for the treatment of osteoporosis is the use of anabolic agents to promote bone formation and increase bone mass. This class of agents is expected to restore bone to the established osteoporotic skeleton.
Intracellular receptors (IRs) form a class of structurally-related genetic regulators scientists have named "ligand dependent transcription factors." (R. M. Evans, 240 Science, 889 1988). Steroid receptors are a recognized subset of the IRs, including the androgen receptor (AR). Regulation of a gene by such factors requires both the IR itself and a corresponding ligand which has the ability to selectively bind to the IR in a way that affects gene transcription.
U.S. Pat. No. 5,696,130 discloses certain tricyclic non-steroidal compounds which are modulators for steroid receptors. The androgen receptor mediator compounds of the '130 patent are disclosed as useful for the treatment of, for example, muscle wasting. One compound disclosed is compound no. 414 (Example 314) R/S-4-Ethyl-1,2,3,4-tetrahydro-6-trifluoromethyl-8-pyranono[5,6-g]quinolin e.